The overall aim of this research program is to develop an optimal oligonucleotide drug to specifically modulate cancer-associated mRNA in superficial bladder cancer. Bladder cancer represents a significant health problem with 53,000 new cases and 12,000 deaths per year in the US and a high failure rate of available therapies. In Phase I we are talking a broad approach with regard to the choice of oligonucleotide type (antisense, hammerhead ribozyme, external guide sequence, DNA enzyme) and intend to evaluate four different chemical modifications of these oligomers. Each of the combinations will be tested in a well-characterized tissue culture model of superficial bladder cancer using two oligonucleotide delivery reagents. The best oligomer determined from the above experiments will be synthesized in large scale and then tested in mouse orthotopic Implantation xenogralt and endogenous models of superficial bladder cancer. In Phase fl we will evaluate the toxicity profile and continue to study efficacy, bioavailability and delivery of the oligomer with the aim of ultimately entering a human trial. Combination treatments of oligonucleotide with existing drugs will be evaluated PROPOSED COMMERCIAL APPLICATION: The immediate application is the development of a therapeutic for bladder cancer, either alone or as part of a combination drug therapy. The rate of appearance of bladder cancer is 53,000 new cases per year; the revenues for a widely used drug are estimated at $0.5bL. The oligonucleotides discovered in this application could also be used to dissect the role of apoptosis in oncogenesis. The overall technology is further applicable to the general area of functional genomics.